1. Field of the Invention
The present invention relates to an antagonist peptide of interleukin-6 (IL-6), which is able to specifically compete for the binding of IL-6 to its receptor and inhibits IL-6-mediated tumor growth.
2. The Prior Arts
Interleukin-6 is a pleiotropic secreted cytokine with a molecular weight of 22–27 kDa. The physiological activities of IL-6 are known to be mediated through binding to a membrane-bound glycoprotein IL-6 receptor (IL-6R) α chain protein (gp80) on target cells to process regulation. The IL-6/IL-6R complex, formed after the binding of IL-6 and IL-6R, activates the 1-chain protein of IL-6R (abbreviated hereafter as gp130) to express many biological functions. The IL-6/IL-6R complex initiates dimerization of gp130 from monomers, activates a cytoplasmic tyrosine kinase bound to gp130 of target cells, and then triggers 3 main signaling pathways, including Janus-activated kinase/signal transducers and activators of transcription (Jak/STAT), Ras/mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3-K)/Akt signaling.
In addition, gp80 may be cleaved from the cellular membrane molecule by a transmembrane metalloproteinase or translated from an alternatively spliced mRNA to form a soluble receptor (sIL-6R). This soluble receptor binds IL-6 with an affinity similar to that of the receptor on the cellular membrane. And more importantly, the sIL-6R/IL-6 complex is capable of activating cells via interaction with membrane-bound gp130 to initiate the abovementioned signaling pathways. This unique feature makes the sIL-6R/IL-6 complex an agonist rather than an antagonist for target cells. On the other hand, elevated sIL-6R levels have been proved in numerous clinical conditions, indicating that the production of sIL-6R is part of the process in many diseases.
Through binding to gp130, IL-6 triggers various signal transductions, results in many different biological functions such as regulating inflammation, immuno-responses, hepatic acute-phase protein synthesis, and other important physiological functions. Most importantly, IL-6 signaling mediated via gp130 has been proved to interfere with many cellular functions, such as cell apoptosis, cell differentiation, cell migration and tumor angiogenesis, etc. And it is also critically implicated in the pathogenesis of various human cancers, including multiple myeloma, Kaposi's sarcoma, prostate cancer and cervical cancer.
As mentioned above, IL-6 plays a pivotal role in many disease processes. With the progress in molecular biology and the understanding in IL-6, IL-6R and their signaling pathways, using IL-6R as a molecular target shows great potential in the clinical applications. Therefore, Trikha M. et al. have suggested (Clin. Cancer Res. 2003; 9: 4653–4665) the feasibility of targeting-IL-6R cancer therapy, which used anti-IL-6 monoclonal antibodies to block IL-6 dependent processes. However, because of the complicated ways of preparation and high production cost of monoclonal antibodies, people who skilled in the art will understand that the use of monoclonal antibodies is limited in industrial application.